Investigation of genes important in neurodevelopment disorders in adult human brain

• Published in: Human genetics Vol. 134; no. 10; pp. 1037 - 1053
• Main Authors: Maussion, Gilles, Diallo, Alpha B., Gigek, Carolina O., Chen, Elizabeth S., Crapper, Liam, Théroux, Jean-Francois, Chen, Gary G., Vasuta, Cristina, Ernst, Carl
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2015; Springer; Springer Nature B.V
• Subjects: Adult; Analysis; Autism; Base Sequence; Biomedical and Life Sciences; Biomedicine; Brain; Cell Line; Consensus Sequence; Disease; Frontal Lobe - metabolism; Frontal Lobe - pathology; Gene Expression; Gene Expression Regulation; Gene Function; Gene Ontology; Genes; Genomes; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Human Genetics; Humans; Hypotheses; Intellectual disabilities; Investigations; Matrix Attachment Region Binding Proteins - genetics; Matrix Attachment Region Binding Proteins - metabolism; Metabolic Diseases; Middle Aged; Molecular Medicine; Mutation; Neural Stem Cells - physiology; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - metabolism; Neurodevelopmental Disorders - pathology; Original Investigation; Stem cells; Transcription Factor 7-Like 2 Protein - genetics; Transcription Factor 7-Like 2 Protein - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Young Adult; Canada; Montreal Quebec Canada; Autism Spectrum Disorder; Neural Stem Cell; Adult Brain; Fetal Brain; Adult Human Brain
• DOI: 10.1007/s00439-015-1584-z
• ISSN: 0340-6717

Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs , SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs. Analysis of DNA interaction sites in neural stem cells reveals high (40–50 %) overlap between proliferating and differentiating cells for each gene in temporal space. Studies in adult brain demonstrate that consensus sites are similar to NSCs but occur at different genomic locations. We also performed expression analyses using BrainSpan data for NDD-associated genes SATB2 , EHMT1 , FMR1 , MECP2 , MBD5 , CTNND2 , RAI1 , CHD8 , GRIN2A , GRIN2B , TCF4 , SCN2A , and DYRK1A and find high expression of these genes in adult brain, at least comparable to developing human brain, confirming that genes associated with NDDs likely have a role in adult tissue. Adult function of genes associated with NDDs might be important in clinical disease presentation and may be suitable targets for therapeutic intervention.